Determination of misoprostol acid in plasma samples by UPLC-MS/MS with application in a maternal-fetal pharmacokinetic study following a low misoprostol dose vaginally to induce labor.

Misoprostol is a prostaglandin E1 synthetic analogous used for elective interruptions of early pregnancy, treatment of incomplete abortion, postpartum hemorrhage and induction of full-term labor. Its a lipophilic drug, passing by extensive and rapid pre-systemic metabolism into the active metabolite, misoprostol acid (MA). The objective of this study was to develop and validate a highly sensitive method for MA determination in plasma using UPLC-MSMS, with application in a study of maternal-fetal pharmacokinetics in healthy parturients women (n = 10) after administration of 25 µg misoprostol vaginally. The method presented linearity of 2-10 pg/mL and acceptable precision, accuracy, plasma and solution stability. The parturients women presented median (interquartile range) values of AUC0-6 of 68.0 (40.8-84.7) pg.h/mL, Cmax of 21.9 (11.9-30.1) pg/mL and Tmax of 2.25 (0.69-5.00) h. The placental transfer of MA was assessed from the umbilical vein/maternal blood ratios of 1.40 (0.91-2.13) and intervillous space/maternal blood ratios of 0.49 (0.15-3.41). In conclusion, this method presented high sensitivity, being able to quantify MA in plasma samples following a low 25 µg misoprostol administered vaginally aimed to induce labor in parturients women. Additionally, this is the first description of the placental transfer of MA after a vaginal administration of misoprostol.

ABCG2 c.421C>A polymorphism alters nifedipine transport to breast milk in hypertensive breastfeeding women.

Nifedipine, a known substrate to breast cancer resistance protein (ABCG2/BCRP), is used for the treatment of hypertension during breastfeeding. This study aimed to evaluate the effect of ABCG2 c.421C>A on nifedipine transfer to breast milk (BM) in hypertensive women. Nineteen hypertensive breastfeeding women treated with 20 mg nifedipine every 12 hours were investigated. Blood and BM samples were collected simultaneously 15-30 days after delivery and at least 15 days after drug treatment. Patients genotyped as ABCG2 c.421CC showed nifedipine plasma and BM concentrations ranging from 8.32-178.1 ng/mL and 4.8-58.5 ng/mL, respectively. ABCG2 c.421C>A showed a trend towards significance (p = 0.0793) on nifedipine in BM, with concentrations approximately 3 times higher in the heterozygous 421 CA (29 ng/mL) in comparison to 421 CC (10.5 ng/mL). Nifedipine BM/plasma ratio was significantly lower in 421CC when compared to 421CA (p = 0.01). In conclusion, ABCG2 c.421C>A polymorphism is associated with higher transfer of nifedipine to BM.